CA2161662C - Process for preparing intermediates for the synthesis of antifungal agent - Google Patents

Process for preparing intermediates for the synthesis of antifungal agent Download PDF

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Publication number
CA2161662C
CA2161662C CA002161662A CA2161662A CA2161662C CA 2161662 C CA2161662 C CA 2161662C CA 002161662 A CA002161662 A CA 002161662A CA 2161662 A CA2161662 A CA 2161662A CA 2161662 C CA2161662 C CA 2161662C
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compound
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treating
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CA2161662A1 (en
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Anil K. Saksena
Viyyoor M. Girijavallabhan
Russell E. Pike
Haiyan Wang
Raymond G. Lovey
Yi-Tsung Liu
Ashit K. Ganguly
William Brian Morgan
Aleksey Zaks
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Merck Sharp and Dohme Corp
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Schering Corp
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    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
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    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract

Disclosed is a process for preparing chiral compounds of formula (I) wherein: X1 and X2 are independently F or Cl; and E is -SO2R2, wherein R2 is C1-C6 alkyl, -C6H4CH3 or -CF3;
its enantiomer and racemates thereof, useful in the synthesis of tetrahydrofuran azole antifungals. Novel compounds of formula (I) or (III) wherein: X1 and X2 are independently F or Cl; B
represents -C(O)Q* or -CH2OR'; Q* represents a chiral auxiliary group; R" represents a hydroxy protecting group; and A represents Cl, Br, I, triazolyl or imidazolyl; are also disclosed.

Description

~ 94125452 PCT/US94104355 ~1 s ~ss~
The present invention comprises a process for preparing chiral intermediates useful in the preparation of tri-substituted tetrahydrofuran triazole or imidazole antifungals.
E~iropean Patent No. 031823481 and USP 5, 039, 676 disclose (~) ~i,~ and (t) traps antifungal compounds of the formula CH2- O ~ ~ ~N- Z
.a ~N
wherein: a is N or CH; X= F or CI; Z=loweralkyi, (C2-C8) alkanoyl or phenyl substituted by 2-loweralkyl-3-oxo-1,2,4-triazol-4-yl, e.g., (t)-~
and (~)-traps-1-[4-[[2-(2,4-difluorophenyi)-2-[(1~-1,2,4-triazol-1-yl)methyl]tetrahydro-4-furanyl]methoxy]phenyl]-4-(1-methylethyl)piperazine.
In addltl0n, copenc~ing Canadian Application No. 2,122, 27o relates to~antifungai compounds of the formula OY
wherein: X is both F or both CI or one X is F and the other is CI; and Y is a group of the formula 'N
2 ~ ~ ~ PCT/US94104355 o s~ ~N- ~ ~ N I
1~J ~r N

a_' ~N _ CH -CsHa-- ~N
(~~)Z

/~ o ;
-CsH~tw N ~ -C~I-~- N S -CsHa_- ~S~
N ; ~ ; ~ ~O
or ~ t1~1- CH(CH3)2 -C61~,,- N
Z
wherein:
R~= (C~-C~o)alkYl, (C2-C~v)alkenyl, (C2-C~o)al~Yl, (C3-Ce)cycloalkyl, or CH2R2; R2 ~ (C~-C3) pefialoalkyl, C02R3, 'CH(OR4)CH20R4 or CH2N(R5)2; R3 = lower alkyl or H; R4 = R3 or (CH2)20R3; R5 = lower alkyl; Z = H or (Ci-C5) alkanoyl; and the carbons with the asterisk (') have the R or S absolute configuration; or a pharmaCBUtICally .~ccwptable salt thereof .
Can . App . No : 2,122, 270 further discloses processes far ire synfh~is of tri-substituted tetrahydrofuran azole antifungals via a tosylate intiate of the formula OTs J
~N
wherein X is as defined above.
The prior art process for preparing the tosylate °~~' ~ Intermediate is inefficient and requires a costly chiral epoxidation to WO 94/25452 ~ ~ ~ ~ PCTIUS94I04355 introduce the proper stereochemistry in the molecule. It was therefore desirable to develop a chiral synthesis of this key intermediate which does not suffer the shortcomings of the prior art process SUMMARY OF THE INVENTION
The present invention comprises a process for preparing compounds of the formula (I) OE
a N (I) wherein: a is CH or N; X~ and X2 are independently F or CI; and E is -S02R6, wherein R6 is C~-C6 alkyl, aryl, substituted aryl or -CF3;
comprising the steps:
(a) cyclizing a chiral alcohol of the formula (II) X' H ~ O
..
R

off (II) wherein X~ and X2 are as defined above, and R is a hydroxy protecting group selected from -CH2-C6H5, tetrahydropyran-2-yl or -C(O)RD, wherein R~ is Ci-C6 alkyl, aryl or -(CH2)~C02H wherein n is 1, 2, 3 or 4, by treating with a halogen and a base to form a chiral halide of the formula (III) -o R
(III) ....
WO 94/25452 PCTlUS94/04355 wherein X~, X2 and R are as defined above, and X3 is CI, Br or I; and (b) treating the halide of formula (III) of step (a) with an alkali metal triazole or imidazole to form a chiral compound of the formula (III), wherein X3 is imidazolyl or triazolyl; removing the protecting group R to form an alcohol of the formula (III), wherein X3 is triazolyl or imidazolyl, and R is H; and treating the alcohol with a compound of the formula E-X, wherein X is CI or Br, and E is as defined above, to form the compound of formula (I); or (bi) removing the protecting group R from the halide of formula (III) of Step (a) to form an alcohol, wherein R is H; treating the alcohol with an alkali metal triazole or imidzole to form a chiral compound of the formula (III), wherein X3 is triazolyl or imidazolyl, and R is H; and treating the alcohol with a compound of the formula E-X, wherein X is CI or Br, and E is as defined above, to form the compound of formula (I).
The present invention further comprises a process, designated Process A, wherein R is -C(O)RD, and the starting compound of formula (II) of Step (a) is prepared by selectively esterifying a prochiral diol of the formula (IV) X~ OH

off (IV) with an effective amount of a mild acylating agent in the presence of an enzyme to form a chiral hydroxy ester of the formula (IIa) X' H ',~ O
R' O
'' off (IIa) wherein X~, X2 are as defined above and Ri is C~-C6 alkyl, aryl or -(CH2)~C02H wherein n is 1, 2, 3 or 4.
Alternatively, the selective esterification of the prochiral diol of formula (IV) is achieved via a process comprising the steps:

~161662-(i) esterifying the prochiral diol of formula (IV) with an amount of an acylating agent effective to form a diester of formula (V) n R' O
R' O
(V) wherein X~ , X2 and R~ are as defined above; and (ii) stereoselectively hydrolyzing the diester of formula (V) of step (i) in the presence of an enzyme to form a chiral hydroxy ester of the formula (IIa) X' H '~. O
R' '' off (IIa) wherein X~, X2 and R~ are as defined above.
The present invention also further comprises a process according to Process A wherein the prochiral diol of formula (N) is prepared via a process comprising the steps:
(A1 ) converting an allylic alcohol of the formula (VI) X' OH
~,/
(VI) wherein X~ and X2 are as defined above, to a compound of the formula (VII) x' L' (VII) ~16166~
wherein X~ and X2 are as defined above and L~ is a leaving group selected from halogeno, -OS02CF3 and -OS02R6, wherein Rs is as defined above;
(A2) reacting the compound of formula (VII) of Step (A1) with an amount of an alkali metal salt of the anion derived from a di(C~-C6 alkyl)malonate effective to form a diester of the formula (VIII) X' C02R2 /
(VIII) wherein X1 and X2 are as defined above, and R2 is C~-C6 alkyl;
(A3) treating the diester of formula (VIII) of Step (A2) with an amount of a hydride reducing agent effective to form the prochiral diol of formula (IV).
In an alternative embodiment, designated Process B, the present invention comprises a process for preparing chiral compounds of formula (II), wherein R is -CH2-C6H5, for use in preparing compounds of the formula (I), comprising the steps:
(B1) reacting a compound of the formula (IX) x' a.
o wherein X~ and X2 are as defined above and Q* is a chiral auxilary group, with a compound of the formula C6H5CH2-O-CH2L, wherein L is a leaving group selected from Cl, Br and I, in the presence of TiCl4 and a tertiary amine base, in amounts effective to form a chiral compound of the formula (X) WO 94/25452 PCTlUS94/04355 ~~ s 1ss~
_,_ ICH2Cs Hs Xi O~
H
~a wherein X~, X2 and Q* are as defined above; and (B2) treating the product of formula (X) of Step (B1 ) with an amount of LiAIH4 effective to form a chiral compound of the formula (II), wherein R is -CH2C6H5.
The present invention further comprises a process according to Process B wherein the starting compound of formula (IX) X' to is prepared by a process comprising the steps:
(B3) heating an allylic alcohol of the formula (VI) X' OH
/
X2 ~
(VI) wherein Xi and X2 are as defined above, with an effective amount of an orthoester of the formula CH3C(OR2)3 , wherein R2 is Ci-C6 alkyl, and a catalytic amount of R2C02H, wherein R2 is as defined above, followed by treatment with an amount of a hydroxide base effective to form an acid of the formula (XI) x, ~ ~ C02H

(XI) ~~s~ssz wherein X~ and X2 are as defined above; and (B4) treating the acid of formula (XI) of step (B3) with an effective amount of an activating agent, then with an alkali metal salt of the formula M+ -Q*, wherein M+ is an alkali metal cation and -Q* is the anion derived from a compound of the formula HQ*, wherein Q* is as defined above, to form a compound of the formula (IX).
Alternatively, the acid (XI) of step (B3) is prepared by reacting 1-(X~)-3-(X2)-benzene, wherein X~ and X2 are as defined above, with succinic anhydride in the presence of a Lewis acid to form a keto acid of the formula x' o ~ ~ co2H
x2 which is treated with CH3~P(C6H5)3~Br and a nonaqueous base to form the acid (XI) for use in step (B4).
In a second alternative embodiment, designated Process C, the present invention comprises a process for preparing compounds of the formula (I) wherein the chiral halide of formula (III) of Step (a), wherein R is H, is prepared by a process comprising the steps:
(C1 ) treating a compound of the formula (IX), as defined above, with effective amounts of S-trioxane, TiCl4 and a tertiary amine base to form a chiral compound of the formula (XII) o~
(XII) wherein X~, X2 and Q' are as defined above;
(C2) cyclizing a compound of the formula (XII) of Step (C1 ) by treating with effective amounts of a halogen and a base to form a chiral halide of the formula (XIII) ~ s~ssz _g_ O
H ,,I~
,~~ Q
X' ' ~O
~ X3 (XIII) wherein X3 is CI, Br or I, and X~, X2 and Q' are as defined above;
(C3) treating the chiral halide of formula (XIII) of Step (C3) with an amount of a hydride reducing agent effective to form a chiral halide of the formula (III), wherein R is H.
The process of the present invention can also be used to prepare compounds of the formula (XIV) X~ O E
x2 ' "
(XIV) wherein a, X~, X2 and E are as defined above, i.e., enantiomers of compounds of the formula (I), by utilizing a chiral auxilary of the opposite configuration, or by the choice of an enzyme which selectively produces the R-enantiomer of a compound of the formula (II), e.g. a compound of the formula (XV) O~ R
i wherein X~, X2 and R are as defined above.

21~1~6~

The present invention further comprises a process for converting compounds of the formula (XV) to compounds of the formula (II) by protection of the free hydroxy group using a suitable protecting group Ra, and selective hydrolysis of the -OR group to form a compound of the formula (XVI) X' H ;~ O

OH
(XVI) wherein X~ and X2 are as defined above and Ra is a hydroxy protecting group. Preferably Ra is -CH2C6H5, tetrahydropyran-2-yl or -C(O)RD, wherein R~ is as defined above, provided that R ~ Ra, in which case compounds of formula (XVI) are compounds of the formula (II).
In an alternative embodiment, the process of the present invention further comprises a process designated Process D for preparing a compound of the formula (I) wherein the chiral halide of Step (a), being a compound of the formula (III) wherein R is -C(O)RD, and R~ is C~-C6 alkyl, is prepared by a process comprising the steps:
(D1 ) esterifying a chiral alcohol of the formula (II) X' H O
R
OH
(II) wherein X~ and X2 are as defined above, and R is -CH2-C6H5 , by treating with an effective amount of an acylating agent to form a chiral compound of the formula (XIX) y R
)~ R' O
( ~1 s ~ss~

wherein X~, X2 are as defined above, R is -CH2C6H5, and R~ is C1-C6 alkyl; and (D2) cyclizing the chiral product of formula (XIX) of Step (D1) by treating with a halogen to form a chiral halide of formula (III) R

(III) wherein X~, X2 are as defined above, R is -C(O)RD, R~ is C~-C6 alkyl, and X3 is CI, Br or I.
The present invention also further comprises chiral compounds of the formula (XVII) or (XVIII) H H
' B ~. B
X' '~ X' R S
'',....
O / O
X2 A Or X2 A
(XVII) (XVIII) wherein:
X~ and X2 are independently F or CI; A represents CI, Br, I, triazolyl or imidazolyl; B represents -C(O)Q' or -CH20R°; wherein R"
represents a hydroxy protecting group selected from -CH2C6H5, or -C(O)RD, wherein R~ is C1-C6 alkyl, -CH2C6H5 or aryl; and Q' represents a chiral auxilary group selected from chiral oxazolidinones of the formula Rs H R . H
.:
-- N ~ ~--- N
O O
O Or O

_12_ wherein R5 is isopropyl or benzyl, and chiral sultams of the formula N N
or useful as intermediates for preparing antifungal agents.
The process of the present invention is chemically efficient and produces chiral compounds of the formula I in high optical purity.
Therefore, the instantly claimed process does not suffer the shortcomings of the prior art process.
The process of the present invention can also be used to prepare compounds of the formula I in racemic form by utilizing the achiral diol IV in place of a chiral compound of the formula II for the cyclization of Step (a) forming a racemic iodide of formula III wherein R
is H. No deprotection is necessary in Step (b) where an iodide III, wherein R is H, is used.
DETAILED DESCRIPTION
The process of the present invention utilizes a chiral auxilary group, or alternatively an enzyme, to stereoselectively produce chiral compounds from achiral starting materials. The stereochemical designations represented by -~~~ and ~~~~~~~~i bonds denote both absolute stereochemistry and, where more than one chiral center is present, relative stereochemistry. The optical purity of compounds is generally given in terms of the enantiomeric excess (e.e.) of the indicated stereoisomer.
In the process of the present invention, where a chiral auxiliary is used to form a single enantiomer of a compound, the opposite enantiomer can be prepared by utilizing the opposite enantiomer of the chiral auxiliary employed. Similarly, where an enzyme is used to prepare a chiral compound from a prochiral starting ~~ s ~ss2 material, the specific enantiomer obtained is controlled by selection of the proper enzyme.
As used herein the term "alkyl" means a straight or branched alkyl chains of 1 to 6 carbon atoms;
"aryl" means a C6-Ci o carbocyclic aromatic group, such as phenyl or naphthyl; and "substituted aryl" means an aryl group having 1 to 3 substituents selected from halogeno, C~-C6 alkyl, N02 or CF3;
"hydroxide base" means LiOH, KOH, NaOH, Ca(OH)2;
"base" means pyridine, NH40H, Na2C03, K2C03, NaHC03 or KHC03;
"nonaqueous base" means a non-nucleophilic reagent capable of generating a carbanion, such as NaN[Si(CH3)3)2, KN[Si(CH3)sl2 and LiN[CH(CH3)2)2~
"tertiary amine base" means Et3N or Hunigs base;
"alkali metal triazole or imidazole" means an alkali metal salt of the anion derived from triazole or imidazole, respectively, e.g., sodium triazole, potassium triazole, lithium triazole, sodium imidazole, potassium imidazole or lithium imidazole;
"hydride reducing agent" means LiAIH4, NaBH4, LiBH4, NaBH3CN;
"halogen" means C12, Br2 or 12; "halogeno" means a chloro, bromo or iodo group; and "halide" means a chloride, bromide or iodide anion or substituent;
"brominating agent" means a reagent capable of converting an alcohol to a bromide, preferably PBr3;
"activating agent" means a reagent capable of converting a carboxylic acid into a reactive derivative, such as an acid halide, anhydride or a mixed anhydride, preferably reagents such as SOC12, oxalyl chloride, carbonylditriazole or oxalylditriazole;
"alkali metal salt" means a salt comprising a cation derived from Li, Na or K, and an anion;
"sulfonylating agent" means a reagent capable of converting an -OH group into a sulfonyl group of the formula -OS02R6, wherein R6 is C~-C6 alkyl, aryl, substituted aryl or -CF3, preferably a reagent such as tosyl chloride or mesyl chloride h vw0 94/25452 ~ ~ ~ PCTIUS94l04355 'leaving group' means a substituent which is readily displaced by a nucleophile, such as CI, Br, I or -OS02R6, wherein R6 is C~-Cs alkyl, aryl, substituted aryl or -CF3;
'Lewis acid' means a reagent capable of catalyzing a Friedel-Crafts acylation reaction, including reagents such as AIC13, BF3, SnCl4, BC13 or ZnCl2;
'acylating agent' means a reagent of the formula v R~-C(O)-Z, wherein R~ is C~-Cs alkyl, and Z is a suitable leaving group, such that said acylating agent is capable of reacting with the hydroxy group of an alcohol to form an ester; preferred are acylating agents selected from acid chlorides, acid anhydrides or mixed anhydrides, and most preferably a reagent such as butyric anhydride, acetyl chloride or acetic anhydride;
'mild acylating agent' means a reagent that is used in combination with an enzyme to transfer an acyl group to a substrate bearing a hydroxy group; such reagents include: succinic anhydride;
esters of the formula R~-C(O)-OR3, wherein R3 is trifluoroethyl, Ci-C6 alkyl or C2-Cs alkenyl, and preferably the ester is vinyl butyrate, vinyl acetate, vinyl benzoate, isopropenyl acetate, methyl acetate, ethyl acetate, isopropyl acetate, trifluoroethyl acetate, trifluoroethyl butyrate, trifluoroethyl isobutyrate or trifluoroethyl 2-methylbutyrate, with vinyl acetate being most preferred; and acetic anhydride.
Enzymes for use in the present invention are selected from enzymes capable of stereoselectively hydrolyzing a symmetrical prochiral diester, or alternatively catalyzing the esterification of a symmetrical prochiral diol, such that a single chiral hydroxy ester is formed in high e.e. Enzymes for use in the process of the present Invention include the commercially available enzyme preparations Identified in Table 1 of Example 4 below. The preferred enzymes are po*cine pancreatic lipase, Amano CE (Humicloa lanugiosa), Ama*o AY-30, Biocatalysts H. lan~giosa, Biocatalysts M. meihei, Biocatalysts Ps.*
fluorescens, Meito MY; Meito PL, Novo Lipozyme IM-20*; Novo SP435 (Candida antartica,) (Novozyme 435). Most preferred are Amano CE
and Novo SP435 (Novozyme 435).
* Trade-marks ls~ss~

The chiral auxilary "Q*" is a chiral oxazolidinone of the formula R5 rH R .: H
~N ~ ~--N
O O
0 or o wherein R5 is isopropyl or benzyl, as disclosed by Evans et al, in ~
Amer. Chem. Soc., 1~, 2127-2129 (1981 ) and Tetrahedron, 44, 5525-5540 (1988); or a chiral sultam of the formula N N
or as disclosed by Oppolzer et al, ,I. Amer. Chem. Soc., 11~, 2767-2772 ( 1990).
As used herein the following reagents and solvents are identified by the abbreviations indicated: methanol (MeOH);
tetrahydrofuran (THF); diethyl ether (Et20); lithium di-isopropylamide (LDA); triethylamine (Et3N); di-isopropylethylamine (Hunigs base); ethyl acetate (EtOAc); ethanol (EtOH); N,N-dimethylformamide (DMF); N,N'-dimethylpropyleneurea (DMPU); 4-dimethylaminopyridine (DMAP);
p-toluenesulfonyl chloride (tosyl chloride or TsCI); methanesulfonyl chloride (mesyl chloride or MsCI); p-toluenesulfonic acid (p-TSA) The following abbreviations are used to identify substituent groups in the structural formulae: tetrahydropyran-2-yl radical (THP); p-toluenesulfonyl radical (Ts); and acetyl radical (Ac).
The present invention comprises a process for preparing a compound of the formula I as shown in Reaction Scheme 1.

~.~.~1~6~
-1 s-Reaction Scheme 1 Step (a) /OAR
_ H O
halogen X~ R
base III
xz Step (b) 1) MN~a~ H = OE
N X~
III 2) deprotection O I
3) E-X
X2 ~ N~ ~
_N
Step (b1 ) 1 ) deprotection OE
H
a 2) M N ~ ~ X~
III ~N
O I
3) E-X ~ ~ a ~N
In Reaction Scheme 1, Step (a), the compound II is reacted with a halogen, such as C12, Br2 or 12, preferably Br2 or 12, in the presence of a base, such as pryidine or NaHC03, in a suitable solvent, such as CH3CN, THF, EtOAc or CH2C12, at -20° to 30°C, preferably about 0° to 25°C, to form the halide III, wherein X3 is CI, Br or I.
In Step (b) the halide III is:

~ s ~ss~_ _, 7_ (1 ) heated with an alkali metal triazole or imidazole (M
represents an alkali metal), such as Na-triazole or Na-imidazole, in a suitable solvent, such as DMF, in the presence of DMPU, at 70° to 100°C, preferably about 80°C, for 10 to 24 h, preferably about 15 h; and (2) deprotected by:
(i) where R is -C(O)RD, treating with a base, preferably K2C03, Na2C03 or NH40H, in a suitable solvent, such as MeOH/water, at 0° to 25°C, preferably about 0° to 5°C; or (ii) where R is tetrahydropyran-2-yl, treating with HCI, preferably a soultion of 10% HCI (aqueous), at 15° to 35°C, preferably about 25°C, for 1 to 6 h, preferably about 3 h; or (iii) where R is -CH2CsH5, hydrogenating under H2 atmosphere in a suitable solvent, such as EtOH, in the presence of a suitable catalyst, such as Pd on carbon, preferebly 10% Pd on carbon, and an acid, preferably HCI;
to form an alcohol wherein R is H; and (3) treated with a compound of the formula E-X, wherein X is a halide, preferably chloride, and E is as defined above, preferably -S02C6H4CH3 Or -SOZC6H4C1, in the presence of a base, such as pyridine, to form a compound of the formula I.
In the alternative Step (b1 ), the halide III is:
(1 ) deprotected by:
(i) where R is -C(O)RD, treating with a base, preferably K2C03, Na2C03 or NH40H, in a suitable solvent, such as MeOH/water, at 0° to 25°C, preferably about 0° to 5°C; or (ii) where R is tetrahydropyran-2-yl, treating with HCI, preferably a solution of 10% HCI (aqueous), at 15° to 35°C, preferably about 25°C, for 1 to 6 h, preferably about 3 h; or (iii) where R is -CH2C6H5, hydrogenating under HZ
atmosphere in a suitable solvent, such as EtOH, in the presence of a suitable catalyst, such as Pd on carbon, preferebly 10% Pd on carbon, and an acid, preferably HCI, according to the procedure disclosed by Freifelder, in "Catalytic Hydrogenation in Organic Synthesis, Procedures and Comments", p. 120, J. Wiley & Sons (1978);

~.~61662 to form an alcohol wherein R is H; and (2) the alcohol is heated with an alkali metal triazole or imidazole (M represents an alkali metal), such as Na-triazole or Na-imidazole, in a suitable solvent, such as DMF, in the presence of DMPU, at 70° to 100°C, preferably about 80°C, for 10 to 24 h, preferably about h; and (3) treated with a compound of the formula E-X, wherein X is a halide, preferably chloride, and E is as defined above, preferably -S02C6H4CH3 or -S02C6H4C1, in the presence of a base, 10 such as pyridine, to form a compound of the formula I.
In the embodiment of Process A, the present invention further comprises a process wherein the chiral compound of formula (II) is a chiral hydroxy ester of the formula (IIa), i.e., a compound of the formula (II) wherein R is -C(O)RD and R~ is as defined above. The 15 chiral hydroxy ester of formula (IIa) is prepared from a prochiral diol of the formula (IV) by using an enzyme to selectively esterify the prochiral diol (IV), thus forming the chiral compound of formula (IIa). The selective esterification is accomplished according to the process shown in Reaction Scheme A.
Reaction Scheme A
ON
O R~
mild acylating O
agent )H
enzyme ~ OH
IIa IV
In Reaction Scheme A, the prochiral diol IV is treated with a mild acylating agent, preferably an ester of the formula R~-C(O)-OR3, wherein R~ is as defined above and R3 is trifluoroethyl, Ci-C6 alkyl or C2-C6 alkenyl, most preferably vinyl acetate, in the presence of an ~~ s~ssz enzyme, most preferably Novo SP435, in a suitable solvent, such as toluene or CH3CN, at 0° to 35°C, preferably about 25°C, to form the chiral hydroxy ester of the formula IIa.
By utilizing other lipase enzymes, such as Amano CE, in the process of Reaction Scheme A, the R-enantiomer, i.e., a compound of the formula XV, as defined above, can be prepared.
The chiral hydroxy ester IIa is alternatively prepared by the process of Reaction Scheme AA.
Reaction Scheme AA
nH ~ R
O
acylal )H a9en~
)~ R
O
IV V
Step (b) O R' O
enzymatic hydrolysis ~ ~H
V
IIa In Reaction Scheme AA, Step (a), the prochiral diol IV is treated with an acylating agent, preferably an acid halide, acid anhydride or mixed anhydride, most preferably butyric anhydride, acetyl chloride or acetic anhydride, in a suitable solvent, such as THF, at 0°C
to 40°C, preferably about 25°C, to form the diester V.
Step (a) WO 94IZ5452 ~ PCT/US94104355 ~16~662 In Step (b), the diester V is treated with an enzyme, preferably a lipase, most preferably Amano CE, in a suitable solvent, such as THF/water, at 15° to 35°C, preferably about 25°C, to form the chiral hydroxy ester IIa.
The present invention further comprises a process according to Process A wherein the prochiral diol IV is prepared by the process described in Reaction Scheme AAA.
Reaction Scheme AAA
Step (A1 ) ", ", brominating off agent or sulfonylating x2 agent VI VII
Step (A2) co2R2 nn+ - < x' co2R2 COzR2 V I I ~ ~ ~ C02R2 VIII
Step (A3) OH
X' hydride reducing agent VIII
x2 ~ OH
IV
In Reaction Scheme AAA, Step (A1 ), the allylic alcohol VI
is treated with a brominating agent, preferably PBr3, in a suitable solvent, such as CH2C12, at -10° to 35°C, preferably at 0° to 25°C, for 30 ls~ssr~

to 90 min, preferably about 1 h, to form an allylic bromide, i.e., a compound of formula VII, wherein L~ is Br.
Alternatively, in Step (A1 ), the allylic alcohol VI is treated with a sulfonylating agent, such as mesyl chloride or tosyl chloride, a tertiary amine base, such as Et3N, and DMAP, in a suitable solvent, such as CH2C12, at -10° to 35°C, preferably 0° to 25°C, to form the sulfonylated product, i.e., a compound of the formula VII wherein L~ is -OS02R6 and R6 is as defined above.
In Step (A2), the compound of formula VII is treated with an alkali metal salt of the anion derived from di(C~-C6 alkyl)malonate, preferably NaCH(C02C2H5)2, in a suitable solvent, such as THF, at 15°
to 35°C, preferably about 25°C, for 1 to 3 h, preferably about 1.5 h, to form the diester VIII.
In Step (A3), the diester VIII is treated with a hydride reducing agent, preferably LiAIH4, in a suitable solvent, such as THF or Et20, at 0° to 35°C, preferably about 25°C, for 1 to 4 h, preferably about 2 h, to form the prochiral diol IV.
Alternatively in Step (A3), the diester VIII is treated with NaBH4, in the presence of LiCI, in a suitable solvent, such as EtOH, at 0° to 35°C, preferably 0° to 25°C, for 1 to 4 h, preferably about 1 ~/2 h, to form the prochiral diol IV.
In the alternative embodiment of Process B, the present invention comprises a process wherein the chiral compound of formula (II) is a chiral benzyl ether of the formula (IIb), i.e., a compound of the formula (II) wherein R is -CH2C6H5. The chiral benzyl ether of formula (IIb) is prepared by the process shown in Reaction Scheme B.
Step (B1) Reaction Scheme B
X~ ~ H2Cs Hs X~ O\
O' TiCl4 H
O

Step (B2) ~ OCH2C6 Hs LiAIH4 -X IIb In Reaction Scheme B, Step (B1 ), a compound of the formula IX is treated with TiCl4 and a compound of the formula C6H5CH20CH2L, wherein L is a leaving group, preferably a halide, in the presence of a tertiary amine base, such as Et3N, at -10° to 10°C, preferably about 0°C, to form a chiral compound of the formula X.
In Step (B2), the chiral compound of formula X is treated with LiAIH4 in a suitable solvent, such as THF or Et20, at 0° to 35°C, preferably about 25°C, to form the chiral benzyl ether IIb.
The present invention further comprises a process according to Process B wherein the compound of the formula IX is prepared by the process described in Reaction Scheme BB.
Step (B3) Reaction Scheme BB
1) CH3C(OC2Hs)s X~
CzHsC02H
OH a -"~ ~ ~ ~ CpzH
2) hydroxide I

VI

WO 94/25452 , PCT/US94104355 ~1 s lss~

Step (B4) x' 1 ) activating ~ O' XI agent 2) M+ .Q~

IX
In Reaction Scheme BB, Step (B3), the allylic alcohol VI is treated with CH3C(OC2H5)3 and a catalytic amount of propionic acid at 90° to 130°C, preferably about 120°C, then treated with a hydroxide base, preferably KOH or NaOH, in a suitable solvent, such as MeOH, preferably MeOH/water, at 15° to 35°C, preferably about 25°C, to form the acid XI.
In Step (B4), the acid XI is treated with an activating agent, preferably SOC12 or oxalyl chloride, at 15° to 35°C, preferably about 25°C, to form a reactive derivative, such as an acid chloride. The reactive derivative is treated with an alkali metal salt of the formula M+ -Q*, preferably the Li+ salt, wherein -Q* is preferably an anion derived from a chiral oxazolidinone of the formula R5 H R% H
r ., _ N O - N O
O Or O
at -70° to 25°C, preferably -70° to 0°C, to form the compound of formula IX.
In the second alternative embodiment of Process C, the present invention comprises a process wherein the chiral halide of formula (III) is a chiral alcohol of the formula (IIIa), i.e., a compound of the formula (III) wherein R is H The alcohol of formula (IIIa) is prepared by the process shown in Reaction Scheme C.

Reaction Scheme C
Step (C 1 ) x' o.
x2 / o IX x11 Step (C2) halogen , base x O
XIII
\ X3 hydride reducing x, agent wo ~ x3 x2 x2 XIII IIIa In Reaction Scheme C, Step (C1 ), the compound of the formula IX is converted to the chiral compound of the formula XII via the general procedure described by Evans et al, J. Amer. Chem. Soc., ,L1"~, 8215-8216 (1990).
In Step (C2), the chiral compound of formula XII is treated with a halogen, preferably Br2 or 12, and a base, preferably pyridine, in a suitable solvent, such as CH3CN, THF, EtOAc or CH2C12, at -20°C to 30°C, preferably about 0°C to 25°C, for 10 to 20 h, preferably about 20 h, to form the chiral halide XIII, wherein X3 is Br or I.
Step (C3) ~~ 6162 In Step (C3), the chiral halide XIII is treated with a hydride reducing agent, such as LiBH4, in a suitable solvent, such as THF or Et20, at -100° to 30°C, preferably starting at -78°C and continuing at 25°C, for 1 to 6 h, preferably about 3 h, to form the chiral hydride IIIa.
In the third alternative embodiment of Process D, the present invention comprises a process for preparing a compound of the formula I, wherein the chiral halide of formula (III) is a compound of the formula (IIIb), i.e., the a compound of the formula (III) wherein R is -C(O)RD, wherein R~ is C~-Cs alkyl, aryl or -(CH2)~C20H wherein n is 1, 2, 3 or 4. The halide of formula (IIIb) is prepared by the process shown in Reaction Scheme D.
Step (D1 ) O~ R W
R
>H ~ Rt O
m Step (D2) H _~ O
R' halogen i ~ O
XIX '~ O

IIIb In Reaction Scheme D, Step (D1 ), the chiral alcohol of formula II, wherein R is -CHZCsH5, i.e., a chiral alcohol of the formula IIb, is treated with an acylating agent, preferably acetyl chloride or ~~g'166 acetic anhydride, in the presence of a base, such as pyridine, to form a chiral ester of the formula XIX, wherein X~, X2, R and R~ are as defined above.
In Step (D2), the ester of the formula XIX is treated with a halogen, such as C12, Br2 or 12, preferably Br or I2, in a suitable solvent, such as CH3CN, THF, EtOAc or CH2C12, at -20° to 30°C, preferably about 0° to 25°C, to form the halide IIIb, wherein X3 is CI, Br or I, and X~, X2 and R~ are as defined above.
Compounds of the formula XI can also be prepared from a compound of the formula VII by reacting with the dianion derived from acetic acid as shown below.
X~ O
X
'CH2 O-~ ~ C02H

V I I XI
Diesters of the formula V can also be prepared from a compound of the formula XI by esterification with an alcohol of the formula R20H, wherein R2 is as defined above, using known methods.
The resulting ester XX is deprotonated by treating with base and the resulting anion reacted with a compound of the formula R20C(O)-L, wherein L is a halide leaving group, as defined above.
x~ x~

C02H -~ v 'C02R2 V
XI

O
X~ ~ X~ C02R2 \ ~/ ~ C~R2 \ _ C~R2 base X2 / ~ /
V
Starting compounds of the formula VI can be prepared via known methods.
The following preparations and examples illustrate the process of this invention:

O
Li O N
_;
Dissolve (4S)-(-)-4-isopropyl-2-oxazolidinone (400 mg, 3.1 mmol) in 4 mL of THF and cool to -78°C. Add 2 mL (3.2 mmol) of a 1.6 M solution of n-butyllithium in hexane and stir the mixture for 10 min at -78°C to give a solution of the title oxazolidinone salt.

O~ O
'F
\ N
H
F / O

~~ s~6fi2 Se a:
1 ) CH3C(OC2H5)s C~C02Fi v~ C02H
2) hydroxide OH base F /
Combine the allylic alcohol (6.25 g, 31.53 mmol), triethyl orthoacetate (20.46 g, 126.12 mmol) and 5 drops of propionic acid, and heat the mixture at 120°C, collecting 4 mL of EtOH by distillation.
Continue heating, distilling off the excess triethyl orthoacetate (14 mL) to give a residue. Combine the residue with KOH (3.5 g, 63 mmol), 16 mL
of MeOH and 4 mL of water, and stir overnight (Q 18 h) at room temperature. Dilute the mixture with water and wash with cold CH2C12, then acidify the aqueous layer to pH = 3 by adding 0.1 M HCI. Extract with 3 portions of EtOAc, combine the EtOAc extracts, dry over Na2S04 and concentrate to give 6.75 g of the acid product. MS = 213 (M+H)+
~ ~ co2H
1 ) KOH
/ 2) (COCI)2 ~O
O
+ ~ N H
s) ~ Li O N
O
H
Combine the acid product of Step (a) (0.5 g, 2.36 mmol), KOH (0.13 g, 2.36 mmol) and 5 mL of EtOH, and stir for 2 h at room temperature. Evaporate the solvent to a residue, dissolve the residue in toluene and evaporate to dryness. Add 5 mL of anhydrous Et20, cool to 0°C and add 3 mL of oxalyl chloride and 4 drops of DMF. Stir the mixture at 0°C for 2 h, then filter and concentrate the filtrate in vacuo to a ~~ s ~ss~

residue. Add CH2C12, then co-evaporate the CH2C12 and any residual oxalyl chloride to give the acid chloride.
Dissolve the acid chloride (2.36 mmol) in 4 mL of THF and add the resulting solution to the -78°C solution of oxazolidinone salt from Preparation 1. Stir the mixture for 1 h, then remove the solvent in vacuo to give a residue. Chromatograph the residue (silica gel, 15%-20% EtOAc/hexane) to give 0.26 g of the title compound. MS = 324 (fVl+H)+.

F F
PBr3 \ \

F ~ OH ~ Br F
Dissolve the allylic alcohol (5.37 g, 31.58 mmol) in 50 mL
of CH2C12 and cool the resulting solution to 0° to 5°C. Add PBr3 (1.0 mL, 10.53 mmol), warm to room temperature and stir for 1 h, while monitoring the reaction by TLC (silica gel, 25% EtOAc/hexane). Add 50 mL of ice water, stir for 5 min, separate the layers, and dry the organic layer over MgS04. Concentrate in vacuo to give 6.45 g of the bromide product. MS = 233 M+

nN
>H
F tosyl chloride F
\ Et3N
1H I \ 1 F v F / OTs l ~ ~r Dissolve the allylic alcohol (8.51 g, 50 mmol) in 200 mL of CH2C12, add Et3N (8.36 mL, 60 mmol) and 100 mg of DMAP, then cool the mixture to 0° to 5°C. Add tosyl chloride (10.49 g,_55 mmol), then warm slowly to room temperature. Add 1 mL of MeOH, stir for 20 min, and wash with 100 mL of water, then 100 mL of brine. Dry the organic layer over MgS04, then concentrate in vacuo to give 13.1 g of the tosylate product. (Ts = -SO2C6H4CH3).
Step F NaCH(COCzHS}2 F C02C2H5 OTs F / F /
Combine diethyl malonate (1.85 g, 11.6 mmol) and 25 mL
of THF, cool to 0° to 5°c, then add 0.339 g (8.48 mmol) of 60%
NaH (oil dispersion) and stir the mixture at room temperature for 30 min. Add the tosylate of Step (a) (2.50 g, 7.71 mmol) and stir at room temperature for 90 min. Add 250 mL of Et20 and 100 mL of water, stir for 10 min, separate the layers and wash the organic layer with 50 mL of brine. Dry over MgS04, then concentrate in vacuo to give 3.2 g of the di-ester product. MS = 313 M+
Following substantially the same procedure, the allylic bromide of Preparation 3 is converted to the same di-ester product.
OH
F C02C2H5 LiAIH4 v \ C~ZC2~5 / >H
F
Combine the di-ester of Step (b) (1.68 g, 5.38 mmol), and 15 mL of THF and cool the mixture to 0° to 5°C. Add 7.0 mL (6.99 mmol) of a 1.0 M solution of LiAIH4 in THF dropwise over 5 min, then stir the mixture at room temperature for 2 h. Cool the mixture to 0° to 5°C, add 0.3 mL of water dropwise, then add 0.3 mL of 15% NaOH, followed by ~~ s ~ss~

an additional 0.9 mL of water, and stir at room temperature for 1 h.
Filter, concentrate the filtrate in vacuo to a residue, dissolve the residue in 50 mL of CH2C12 and dry over MgS04. Concentrate in vacuo to give 1.10 g of the title compound. MS = 229 M+

LiBH4, OH
F C02C2H5 (NaBH4 + F
LiCI) \ v~ C02C2H5 \

/ ~ / off F F
Combine the diester product of Preparation 3, Step (b) (6.77 g, 21.7 mmol), LiCI (2.76 g, 65.1 mmol) and 100 mL of EtOH, cool to 0° to 5°C, then add NaBH4 (2.46 g, 65.1 mmol), then slowly warm the mixture to room temperature and stir overnight. Add 100 mL of MeOH
and 100 mL of water, stir for 90 min, then concentrate in vacuo to a residue. Partition the residue between 500 mL of EtOAc and 100 mL of water, wash the organic layer with 100 mL of brine, dry over MgS04, and concentrate in vacuo to give 4.94 g of the diol product.

F F
\ ~/ ~ C02H ' O
N
O O
The acid of Preparation 2, Step (a) is reacted according to the general procedure taught by Evans et al, Tetrahedron, 44, 5525-5540 (1988) and Gage et al, r . n., ~$, 83-90 (1989) to give the chiral oxazolidinone product, [aJp = - 44.4° (c = 1.67, CHC13). MS =

(M+H)+

WO 94/25452 ~ PCT/US94104355 nr-.r0)C4Hs OC(O)C4Hs Combine 8.5 g of the diol (IV) of Preparation 4 or 5 and 50 mL THF, add 14 mL of butyric anhydride (1.15 equiv.), 15 mL Et3N, and 0.22 g of DMAP, and stir the mixture at 20° to 23°C for 16 h.
Concentrate in vacuo to a residue, dissolve the residue in EtOAc, wash with saturated aqueous Na2C03, then dry over MgS04. Concentrate in vacuo to give the dibutyrate product in near quantitative yield.
Using acetic anhydride and substantially the same procedure the following compound can also be prepared in near quantitative yield:
n~r0)CH3 oc(o)cH3 preparation 7A

F
~ ~ C02H
Steo ~;, Combine 8.5 g of succinic anhydride and 30 g of 1,3-difluorobenzene, add 29.2 g of AIC13 (anhydrous) and stir while heating at reflux for 1 h. Cool to room temperature and stir for 2 h, then add 25 mL of water. Extract with EtOAc, dry the extract over MgS04 and ~ s ~ s s,~

concentrate in vacuo to a residue. Crystallize the residue from EtOH, or a mixture of CH2C12 and hexane, to give 16.6 g of the keto acid product.
to b Combine 876 mg of CH3~P(C6Hs)3~Br and 5 mL of THF, then add 2.6 mL of 1 M NaN[Si(CH3)sls in THF and stir at room temperature for 30 min. Cool the mixture to -78°C and slowly add (dropwise) a solution of 250 mg of the product of Step (a) in 5 mL of THF. Stir the mixture for 12-18 h, then add an aqueous solution of citric acid while cooling to 0°C. Extract with EtOAc, dry the extract over Na2S04, and concentrate to a residue. Purify the residue by chromatography (silica gel, 5% MeOH/CH2C12) to give 142 mg of the title compound, (for use in Preparations 2 and 6).

/ OCH2Cs Hs F
H
OH
/
F ~O
IN
i H
/ O
TiCl4 CsHsCH2 ~ O
F ~O
Et3N H
C6H5CH20CH2C1 ~ N H

Combine the product of Preparation 2 (2.8 g, 8.66 mmol) and 12 mL of CH2C12 and cool the mixture to 0°C, stir the mixture, and add 9.1 mL (9.1 mmol) of a 1.0 M solution of TiCl4 dropwise. Stir for 5 min more. then add Et3N (1.27 mL, 9.1 mmol) dropwise and stir for 1 h at 0°C. Slowly add benzyl chloromethyl ether (3.15 g, 18.2 mmol) and stir the mixture at 0°C for 3 h. Quench with 15 mL of saturated NH4C1, extract with CH2C12, dry the extract over Na2S04, then concentrate in vacuo to a residue. Purify the residue by column chromatography (silica gel, 10% EtOAc/hexane) to give 3.21 g of the product. MS = 444 (M+H)+

O O
F
H C6H$ CH20 N
H Li~ F
H
p ~ ~ OH
F
Reduce the producrof Step (a) by treating with LiAIH4 according to the procedure described by Evans et al., J. Amer. Chem.
~, ~, 1737-1739 (1982) to give the S-isomer of the chiral product, [aJp = -28.4° (c = 1.18, CHC13). MS = 341 (M+Na)+

OTs H~~
F S
,..... O
N- N
F
N

WO 94/25452 ~ ~ ~ 1 fi 6'2 PCT/US94104355 ~tep~a~_ OH ~3C(O)CH3 )H )H
Combine the diol product of Preparation 4 or 5 (0.60 g) and 12 mL of EtOAc, add 1.8 g of porcine pancreas lipase (EC3.1.1.3), de-gas the mixture, and stir at room temperature for 48 h under nitrogen.
Filter the mixture, wash the solids with EtOAc, then concentrate the combined filtrate and washings in vacuo to a residue. Purify the residue by chromatography (silica gel, 10% to 20% EtOAc/hexane) to give 0.628 g of the R-isomer of the chiral product, [a]o = + 6.2° (c = 1.11, CHC13).
MS = 271 M+. 20% to 30% e.e. as determined by ~H NMR using a chiral shift reagent.
F H OC(O)CH3 H~~
F
/ I
OC(O)CH3 Combine the product of Step (a) (0.1 g, 0.37 mmol) and 3 mL of CH3CN, add pyridine (45 ~.L, 0.56 mmol) and 12 (0.188 g, 0.74 mmol) and stir the mixture at 0° to 5° for 6 h. Add 50 mL Et20 and 25 mL
of water, then add a saturated solution of Na2S203 (dropwise) until the mixture is colorless. Stir for 10 min, separate the layers, dry the organic layer over Na2S04, then concentrate in vacuo to a residue. Purify by chromatography (silica gel, 10%-50% EtOAc/hexane) to give 0.132 mg of the chiral iodide. The product is a 90:10 mixture of cis and traps isomers by ~ H NMR.

WO 94/25452 ~ .~ 616 5 2 PCT/US94/04355 t c:
OC(O)CH3 OH
F
Combine the iodide product of Step (b) (0.387 g, 0.908 mmol) and 9 mL of MeOH, add water until the mixture becomes slightly cloudy, then add K2C03 (0.148 g, 1.07 mmol) and stir the mixture at 0°
to 5°C for 1 h. Add CH2C12, wash with water, then dry over Na2S04.
Concentrate in vacuo to a residue then purify the residue by preparative TLC (silica gel, 50% EtOAc/heaxane) to give 0.348 g of the chiral alcohol product (90:10 cis/trans ratio).
Ste,~ (dl:
OH OH
H i~~ Hip.
F ~ F
,.
O \ ~~'''~ O
F , / I F ~ / N_ N
N
Treat the chiral alcohol product of Step (c) with sodium triazole according to the procedure of Example 3, Step (b) to give the chiral triazole product.
Step le):
OH OTs Hi.. Hip.
F ~ F
\ /
v., _ O v..,,. O
/ N- N ~ ~ N- N
F ~~N~ F
N

Treat the alcohol product of Step (d) with tosyl chloride and pyridine as described in Example 6, Step (d) (second paragraph) to form the S-cis isomer of the title compound, [a]p = + 9.5° (c = 1.1, CHC13), in 25% e.e.
Where the chiral iodide of Example 2A is used in Step (c) and carried through Steps (d) and (e), title compound of high optical purity is formed, [a]p = + 37.0° (c = 1.19, CHC13).

OAc C6H5cH2o acetic anhydride C6H5CH20 pyridine H H
OH ~ OAc Combine the chiral product of Example 1 and acetic anhydride in CH2C12, add pyridine and stir at room temperature to form the chiral acetylated product.
I OAc CsH5CH2~
H
OAc WO 94/25452 PCTlUS94104355 166' '~'1 _38_ Treat the acylated product of Step (a) with 12 (a base is not used) according to the procedure of Example 2, Step (b) to form the chiral iodide product.

OTs v ~ N. N
F
~ N
CsH5CH2 ~ C6HSCH2~
F
H , OH
Dissolve the product of Example 1 (1.7 g, 5.34 mmol) in 12 mL of CH3CN, cool the solution to 0° to 5°C and add 12 (2.8 g, 11.0 mmol) and pyridine (1.0 mL, 12.4 mmol). Stir the resulting mixture at 0°
to 5,C for 6 h, then add saturated Na2S203 (aqueous) and Et20 and stir until the mixture is colorless. Extract with Et20, wash the extract with 0.01 N HCI, then with saturated NaHC03, and dry over Na2S04.
Concentrate in vacuo to a residue and purify the residue by column chromatography (silica gel, 0% to 5% EtOAc/hexane) to give 2.3 g of the cyclized iodide, [ajp = + 3.7° (c = 1.17, CHC13). MS = 444 (M+H)+

~~s~ssz Ste b C6H5CH20~ CsHsCH2 \
a . Na N ~ N F
'N
~O
,N
/ N
N
Dissolve the iodide product of Step (a) (1.18 g, 4.01 mmol) in 8 mL of DMF, then add sodium triazole (0.73 g, 8.02 mmol) and 5 drops of DMPU and heat the mixture at 100°C for 30 h. Concentrate In vacuo to a residue, then partition the residue with 100 mL water and 100 mL EtOAc. Extract the aqueous layer with EtOAc, combine the organic layers and dry over Na2S04. Concentrate in vacuo to a residue and chromatograph the residue (silica gel, 20% to 30% EtOAc/hexane) to give the R-cis triazole product, along with the R-trans isomer, i.e., ~ OCH2C6 H5 F
/ N, N
~N
R-cis triazole, 1.0 g, [a]p = - 42.1 ° (c = 1.17, CHC13). MS = 386 (M+H)+
R-trans triazole, 0.24 g, [a]p = + 10.6° (c = 1.12, CHC13). MS =

(M+H)+

Ste c ~ OCH2Cs Hs ~ OTs F ~ F
I
O
\N~N \ ~N
N
~N
'N
Combine the R-cis triazole product of Step (b) (0.83 g, 2.16 mmol), 0.22 g of 10% Pd on carbon, 20 mL of EtOH and 1.2 mL of 1 N
HCI, and agitate the mixture under 60 p.s.i. of hydrogen for 3 h. Filter, concentrate the filtrate to a residue, dissolve the residue in EtOAc and wash with aqueous NaHC03. Dry the EtOAc solution over Na2S04, concentrate in vacuo to give the R-cis alcohol product.
Treat the alcohol with tosyl chloride and pyridine as described in Example 6, Step (d) (2nd paragraph) to give the R-cis isomer of the title compound, m.p. = 101 °-102°C, [a]p = -43.9° (c = 1.16, CHC13).

OC(O)CH3 OC(O)CH3 >H ~r )H
Screening of enzymes for the acetylation of the diol (IV) from Preparation 4 or 5 is carried out using a number of commercially available enzymes via the following general procedure. Combine 0.050-0.10 g of diol (IV) and 1.0 ml of toluene or CH3CN, containing 2-10 equivalents of vinyl acetate. Add 0.001 to 0.30 g of the commercial enzyme preparation and stir the mixture at 20° to 23°C. Analyze the reaction mixture by chiral HPLC to determine: the amounts of remaining H'U !4/15451 ~1 s ~ss~
diol (IV), hydroxy acetate (IIa), and. diacetate (of formula V wherein R2 is CH3); and the absolute configuration and e.e. of chlral hydroxy _ . acetate (IIa). The results are summarized in Table 1 below.
TABLE, 1 a Source a ~ Tlme Product composltlvn (°~6) En:yme mDs (hr.) ,.
Amano Acylase53.8 22 41.12 55.76 3.12 R 29 ~

Amano AK 45.2 3.75 0.29 93.04 6.66 R 79 Amano AP-12 47.6 22 83.48 15.96 0.56 R 55 Amano AY-30 50.3 3.75 0.18 58.02 41.80 R 94 Amano CE 47.7 3.75 0.36 92.02 7.62 R 93 Amano CE 50.0 1.66 - 100 - R 97 Amano CES 46.7 3.75 5.07 93.81 1,12 R 71 C 50.8 22 91.96 7.51 0.53 R 37 Amano FAP-1553.6 22 92.12 7.29 0.58 R 30 Arr~ano G 774 22 2.10 86.98 10.92 R 66 M>ano GC-4 47.3 22 69.41 29.85 0.74 S 7 Amano 56.5 94 84.85 15.15 - R 42 LtH ase A-10 Amano MAP-1048.1 22 49.04 49.55 1.41 R 69 Amano N 55.6 22 94.30 5.20 0.50 R 44 .

Amano PGE 63.1 22 85.09 14.06 0.85 R 7 Amano PS-30 51.5 3.75 0.28 92.02 7.70 R 77 Amano R 43.9 22 68.66 29.92 1.41 R 44 Amano 89.0 28.5 70.29 29.5 0.21 R 71 Pe tidase A

Amano 91.7 28.5 3.82 80.95 15.24 R 34 Aminoac lase Amano 20.7 28.5 8.93 90.31 0.76 R 59 Upoproteln LI ase-80 Amano 16.1 28.5 36.07 63.69 0.23 R 63 Lipoprotein Lt ase-200S

Amano 77.3 28.5 78.67 19.52 1.81 S 22 Newlase A

Amano 91.3 28.5 89.92 10.02 0.05 R 51 Protease Amano 105.1 28.5 68.16 31.00 0.84 S 4 Protease B

Amano 92.3 28.5 12.59 85.26 2.15 R 59 Protease M

Btocatatyst 66.7 1.33 - 34.85 65.15 R 45 i i a) The terms Amano, Biocatalysts, Novo, EDC, Genencor, Genzyme, Gist, 1BT, Interspex, rSC, Meito, Nagase, Quest, Scientific Protein, Seikagaki, Sigma, Solway, Toyoba, Wako are all trade-marks.
i / ,, .

Biocatalyst 76.2 42.25 83.81 15.79 0.40 R 51 As . ni er Biocatalyst 67.4 1.33 2.28 74.07 23.65 R 55 C. lindracea Biocatalyst 55.6 42.25 67.47 32.31 0.22 R 45 Chr. viscosum Biocatalyst 81.2 1.33 - 98. 75 1.25 R 9 H.lanu iosa Biocatalyst 64.3 42.25 5.03 88.59 6.38 R 62 M. 'avanicus Biocatalyst 70.7 18 - 73.98 26.02 R 87 M. meihei Biocatalyst 63.5 18 - 58.51 41.49 R 51 P. c clo ium Biocatalyst 65.8 1.33 - 100 - R 99 Ps.fluorescens Biocatalyst 84.1 18 - 82.30 17.70 R 69 Rh. delemar Biocatalyst 96.3 42.25 84.95 15.03 0.02 R 66 Rh. 'a nicus Biocatalyst 135.242.25 88.95 11.05 - R 36 Rh. 'avanicus Biocatalyst 61.7 3.00 88.78 11.22 - R 46 Rh. niveus EDC Protease 131.128.5 76.40 23.40 0.20 R 48 EDC Protease 159.328.5 90.40 9.53 0.07 R 36 EDC Protease 102.328.5 62.99 35.34 1.66 R 17 Bacterial EDC Protease 146.228.5 80.04 19.69 0.27 R 12 Genencor 21.1 28.5 88.27 10.93 0.80 S 27 Acyftransferase Cells C.O.

Genzyme 23.0 94 12.10 65.62 22.28 R 5 C. lindracea Gist Brocades 225.428.5 12.45 85.77 1.78 R 76 Piccantase A

Gist Brocades 96.3 94 58.68 37.12 4.19 S 8 Calf li se Gist Brocades 135.294 67.55 26.59 5.86 S 1 Kid li ase IBT Peptidase 45.0 22 94.97 4.43 0.60 S 25 Interspex Bacterial254.445 27.36 65.53 7.10 S 38 Protease BP1 Grade C

immobilized Interspex Bacterial271.445 15.45 76.49 8.06 S 58 Protease BP2 Grade C

immobilized Interspex Fungal128.645 33.57 61.56 4.87 R 39 Protease FP1 Grade C 6J92 ISC BE1 66.7 94 79.91 19.49 0.59 R 2 _ ISC BP1 55.6 94 76.83 22.96 0.21 R 5 ISC BP1 immob 70.0 94 9.21 77.76 13.03 R 45 ISC BP2 81.2 94 78.16 21.63 ' 0.20 R 5 ISC BP2 immob 63.5 94 46.88 47.41 5.71 S 50 ISC BP3 64.3 45.75 75.79 23.94 0.27 R 4 ISC BP4 76.2 94 96.89 3.11 - S 34 ISC BPG1 65.8 94 81.62 18.18 0.20 R 8 ISC FP1 65.8 94 71.40 28.25 0.35 R 40 Me'tto MY 48.3 3.75 0.15 65.27 34.58 R 95 Meito OF 47.1 3.75 3.00 86.63 10.37 S 8 Meito PL 47.0 3.75 - 11.79 88.21 R 55 Nagase 117.8 28.5 80.93 15.69 3.37 R 24 Dena sin 10-P

Nagase 119.4 28.5 86.41 13.99 0.20 R 17 Denaz me AP

Nagase 87.1 28.5 81.55 17.86 0.59 ? 3 XP-415 Rhino us Novo IM20 61.7 3.00 - 81.53 18.47 R 95 Novo SP 522 100 24 98 2 - -Novo SP 523 100 24 62.93 30.91 5.98 R 67.3 Novo SP 524 100 24 8.49 83.73 5.32 R 91.5 Novo SP 525 100 24 14.21 57.57 26.60 S 26 Novo SP 526 100 - 24 67.39 27.10 2.52 S 52.5 Novo SP435 84.1 3.00 - - 100 -Quest Kid PGE 86.9 28.5 78.71 19.05 2.24 ? 6 IX

Quest 122.6 28.5 91.97 5.531 2.49 ? 23 Lamb PGE IX

Quest 95.0 28.5 77.22 18.94 3.84 S 3 Protease acid Quest 112.1 28.5 97.04 2.92 0.04 R 50 Protease fun al Scient'rfic 175.4 45 0.00 55.33 44.67 R 24 Protein Labs PEC High Li ase Seikagaki Lipase30.0 45 73.27 26.32 0.41 ? 4 Rhino s delemar Sigma Acylase 88.2 - 45 4.20 76.12 19.68 R 32 I
Aspergillus melease Sigma Acylase 19.8 45 80.95 16.81 2.24 S 19 I
Porcine Kidne Sigma Protease147.6 45 69.46 30.36 0.18 S 23 Type IV
Streptomyces saes 'tosus Sigma Protease205.3 45 86.60 12.88 0.52 ? 9 Type XIII
As illus saitoi Sigma Protease23.1 45 85.72 12.11 2.16 S 33 T XXIV bacterial Sigma Protease50.9 45 66.97 25.80 7.22 R 21 Type XXVII

Na arse Sigma Protease238.945 86.29 13.02 0.68 S 44 Type XXXI Baallus licheniformis Sigma PPL 102.55.50 - 93.97 6.03 R 41 Sigma Wheatgerm23 94 86.31 13.51 0.18 R 5 Solvay AFP 116.545 9.08 83.74 7.18 R 40 Solvay PPL 80.4 20 9.69 90.31 - R 29 Toyobo LPL 9.7 3.75 2.96 53.66 43.37 R 29 Toyobo NEP-16051.8 94 68.96 30.71 0.33 S 41 Wako 17.3 45 44.30 39.10 16.60 ? 4 Achromopeptidase Wako Lipase 32.3 45 56.11 43.39 0.49 R 77 PN

Phycomyces nitens Wako Lipase 1.0 45 0.00 64.72 35.28 R 50 B

Pseudomonas fra i * Denotes absolute configuration at the chiral center in (IIa).
~H
)H
)H
Prepare a 0.2 M solution of the prochiral diol in toluene.
Add the diol solution to a mixture of vinyl acetate (5 equivalents) and the commercially available enzyme Novo SP435 (Candida antarctica) (Novozyme 435) and agitate the mixture at 20° to 23°C. Analyze the S
hydroxy ester product as described in Example 4. The results of several GC(O)CH3 such experiments, using the quantities of reagents indicated, are presented in the following table.

PCT/US94104_'~SS
~ls~ss2 diol lipase time % mono e.e.
I (min) ~ acetate 4.9 g 0.54 g 85 87.2 90 6.1 g 0.50 g 190 87.6 89 11.4 g* 0.51 g 210 75.6 94 10.7 g** 1.0 g 80 71.1 96 * This reaction was run using a 0.4 M diol solution in toluene ** This reaction was run using molecular selves to dry the diol toluene solution.
The reaction is also run in a variety of solvents, at a temperature of 0° to 35°C, via substantially the same procedure as described above to give the following results.
Solvent vinyl diol/ Temp, productcomposition (%) acetateenzyme e.e # eguivratio C I V I1a V

iPr20 10.0 4.0 0 5.76 83.85 10.39 91 THF 10.0 4.0 0 2.41 80.65 16.93 87 Dioxane 10.0 4.0 20-23 1.01 74.71 24.26 93 CH3CN 10.0 4.0 0 0 77.06 22.94 98 Acetone 10.0 4.0 0 1.19 83.07 15.74 94 Toluene 10.0 4.0 0 0.86 89.21 9.93 93 tAmyl Alcohol 5.0 4.0 0 35.04 57.56 7.40 91 Preferably the reaction is run using a 0.9 M solution of the prochiral diol and 1.5 equivalents of vinyl acetate in CH3CN at 0° to 5°C.

pH nC(O)CH3 )H )H
F

~16~66'2 The reaction was run using the commercially available enzyme Amano CE (Humicloa lanugiosa) according to the procedure of Example 4A to form the R hydroxy ester. The results of several such experiments are presented in the following table.
diol lipase time % mono e.e.
I f min) I acetate 0.05 0.05 95 97 99 g g 5.3 5.0 g 95 97.3 96%
g 1.0 0.1 g** 930 92.8 91 g 5.0 5.0 g 170 97.6 97 g 7.7 1.0 g** 170 91.3 95 g ** Th e enzyme e ts was used experimen recovered in thes from a previous run and re-used.

F OH ~ OH
F
OH
(racemic) Combine the diol product of Preparation 4 or 5 (0.5 g, 2.19 mmol) and 10 mL of CH2C12, cool to 0° to 5°C, then add Br2 (0.112 mL, 2.19 mmol) and pyridine (0.117 mL, 2.19 mmol) and stir the mixture at 0°
to 5°C for 18 h. Add 25 mL of CH2C12, wash successively with 10 mL of 10% Na2S03, 10 mL of 1 N HCI, and 10 mL of NaHC03, then dry over MgS04. Concentrate in vacuo to a residue and chromatograph the residue (silica gel, 10% EtOAc/hexane) to give 0.59 g of the bromide product. MS = 307 M+

~ OTs .-' F
\ -~O
~ N- N
F
N
(racemic) t a:
~ OH
F OH
F
F
~O
OH -Combine the diol product of Preparation 4 or 5 (3.80 g, 16.6 mmol), 50 mL of CH3CN and 2.0 mL (25.0 mmol) of pyridine, cool the mixture to 0° to 5°C, then add 12 (8.45 g, 33.3 mmol) and stir at 0° to 5°C for 1 h. Add 500 mL of Et20 and 100 mL of 10% Na2S03, stir for 5 min, then separate the layers. Wash the organic layer with 50 mL of 1 N
HCI, 50 mL of 5% NaHC03, and 50 mL of brine, then dry over MgS04.
Concentrate in vacuo to a residue and chromatograph the residue (silica gel, 10% EtOAc/hexane) to give 5.10 g of the racemic iodide product. MS = 354 M+. ~ H NMR indicates the product is a 84%/16%
mixture of trans and cis isomers.
t b:
'~ OH ~ OTH P
F
~_ 1 ~161~6'~

Combine the iodide product of Step (a) (5.00 g, 14.1 mmol) and 50 mL of CH2C12, add 3,4-dihydro-2H-pyran (1.93 mL, 21.2 mmol) and 0.1 g of p-TSA monohydrate, then stir the mixture at room temperature for 2 h. Add 100 mL of CHZC12, wash with 50 mL of 5%
Na2C03 and 50 mL of water, then dry over MgS04. Concentrate in vacuo to a residue and chromatograph (silica gel, 2.5% EtOAc/hexane) to give 5.61 g of the racemic THP ether product. MS = 439 M+
'~ OTH P _~ OTH P
\ O
~ N- N
F
N
Combine the THP ether product of Step (b) (5.54 g, 12.6 mmol) and 60 mL of DMF, add 90% sodium 1,2,4-triazole (2.30 g, 25.2 mmol) and 5 drops of DMPU, then heat the mixture at 90° to 100°C
for 48 h. Cool the mixture to room temperature, concentrate in vacuo to a residue, and partition the residue in 100 mL of water and 100 mL of EtOAc. Extract the water layer with 100 mL of EtOAc, dry the combined EtOAc layers over MgS04, concentrate in vacuo to a residue, then chromatograph the residue (silica gel, EtOAc) to give 4.17 g of the racemic triazole product. MS = 380 M+
OTH P ~ OTs F
\ O
\ N- N ~ ~ N- N
F
N N

Combine the triazole product of step (c) (4:10 g, 12.2 mmol) and 50 mL of 10% HCI and stir at room temperature for 18 h.
Concentrate in vacuo to a residue, dissolve the residue in 150 mL
CH2C12 and 50 mL of water, then add 10% Na2C03 (dropwise) to adjust the aqueous layer to pH = 8. Separate the layers, wash the organic layer with 50 mL of brine, dry over MgS04, then concentrate in vacuo to give 3.02 g of the alcohol.
Combine the alcohol and 30 mL of pyridine, cool the mixture to 0° to 5°C, and add tosyl chloride (2.13 g, 11.1 mmol). Stir the mixture at 0° to 5°C for 18 h, then at room temperature for 18 h.
Concentrate in vacuo to a residue, dissolve the residue in 100 mL of CH2C12, wash with 50 mL of water, 50 mL of 5% NaHC03, and 50 mL of brine, then dry over MgS04. Concentrate in vacuo to a residue and chromatograph (silica gel, EtOAc) to give 3.13 g of the racemic title compound. MS = 450 M+
Substituting p-chlorobenzenesulfonyl chloride for tosyl chloride in Step (d) and following substantially the same procedure as described above gives the p-chlorobenzenesulfonyl analog (6A).
~ OS02C6 H4CI
F ~ .~ 6A

~ N-N
\\
W N~

H
,,.~~~ OH
F
_- o I ~ . N
N
F
~ N

WO 94/25452 _ PCTlUS94104355 21~166~

CsHs CHy~~,. CsHs CH2 F \
O O
N~ - N
O
O
Essentially following the procedure described by Evans et al, J. Amer. Chern. Soc., 112, 8215-8216 (1990), combine the oxazolidinone product of Preparation 6 (2.18 g, 5.88 mmol) and 24 mL
of CH2C12 at 0°C, add 6.5 mL of 1 M TiCl4 in CH2C12. Stir for 5 min, then add 1.12 mL of Hunigs base and stir at 0°C for 30 min. Add a solution of 1,3,5-trioxane (0.67 g, 7.44 mmol) in 5 mL of CH2C12, then add another 6.5 mL of 1 M TiCl4 in CH2C12 and stir at 0° to 3°C for 2.5 h.
Add 10 mL
of saturated NH4C1 and stir for 5 min, then separate the layers and extract the aqueous phase with 20 mL CH2C12. Combine the organic phase and the extract, wash with brine, dry over MgS04, then concentrate in vacuo to a residue. Chromatograph the residue (silica gel, 15% to 25% EtOAc/hexane) to give 1.33 g of the chiral product, [aJp = - 62.9° (c = 1.7, CHC13). MS = 402 (M+H)+

CsHs ~ O
N
p .~~~~ H
N \1 CsHs O
Combine the product of Step (a) (1 g, 2.5 mmol), 0.45 mL
of pyridine and 20 mL of CH3CN, cool to 0°C, then add 1.78 g of 12.
Stir the mixture at room temperature for 20 h, then quench the reaction with dilute aqueous Na2S204. Extract with Et20 (2 X 20 mL), combine the extracts and dry over MgS04. Concentrate in vacuo to a residue then ~1 s ~ss~-- -chromatograph (silica gel, 15% to 25% EtOAc/ hexane) to give 1.18 g of the chiral iodide product (89.8% yield). MS = 528 (M+H)+
O
H
N H '~~''~ OH
F
:~O
~','' H ~ F
\ I CsHs O
F ~ ~ ~I
F v Combine the iodide product of Step (b) (0.9 g, 1.71 mmol) and 35 mL of THF and cool to -78°C, then add 0.85 mL of 2M LiBH4 in THF and stir the mixture for 1 h while warming to room temperature. Stir for 2 h at room temperature, then cool to -10°C and quench by adding saturated aqueous NH4C1. Stir for 0.5 h, concentrate in vacuo to a residue, partition the residue between CH2C12 and water, separate the layers and dry the organic layer over MgS04. Concentrate in vacuo to a residue and chromatograph (silica gel, 15% to 30% EtOAc) to give 0.43 g of the chiral product. MS = 355 (M+H)+
Step OH
~ .''~~ OH
F
O
~ N~
F
~N
Combine the product of Step (c) (0.3 g, 0.85 mmol), sodium triazole (0.86 g, 8.5 mmol) and 5 mL of DMF and heat at 80°C
under nitrogen for 24 h. Cool the mixture, dilute with 50 mL of water and extract with CH2C12 (2 X 40 mL). Combine the extracts, wash with brine, dry over MgS04, then concentrate in vacuo to a residue.

Chromatograph the residue (silica gel, 50% to 75% EtOAc) to give 0.101 g of the title compound. MS = 296 (M+H)+
Unreacted starting material (0.138 g) was also recovered.

OC(O)CH3 / OC(O)CH3 F F H
OC(O)CH3 OH
Prepare a 50 mM solution of KCI in 20% THF/water. Using this solution, prepare 5 mL of a 0.2 M solution of the diacetate product of Preparation 7A. (The pH of the resulting solution is maintained at 7.5 by titration with aqueous NaOH, as needed, throughout the course of the reaction. Add 0.12 g of Amano CE and stir at room temperature for 18 h.
Filter the mixture, wash the filtrate with water, aqueous Na2C03, then brine, and dry over MgS04. Concentrate in vacuo to give the chiral product in 98% e.e., as determined by chiral HPLC.

OC(O)C4H9 / OC(O)C4Hg F
OC(O)C4H9 H OH
v~
Prepare a solution of 7.0 g of the dibutyrate of Preparation 7 in 63 mL of a 50 mM solution of KCI in 20% THF/water. Add 5.0 g of Amano CE and stir the mixture at 22°C, while maintaining the pH at 7.5 by titration with aqueousNaOH using a pH stat, for 6.5 h. Extract the mixture to give an 81.5% yield of the S product in 99% e.e.
The reaction can also be run in water (excluding THF) by substantially the same procedure as described above.

Claims (16)

1. A process for preparing compounds of the formula (I) wherein: X1 and X2 are independently F or Cl; and E is -SO2R2, wherein R2 is C1-C6 alkyl, -C6H4CH3 or -CF3;
comprising the steps:
(a) cyclizing a chiral alcohol of the formula (II) wherein X1 and X2 are as defined above, and R is a hydroxy protecting group selected from -CH2-C6H5, tetrahydropyran-2-yl or -C(O)R1, wherein R1 is C1-C6 alkyl, by treating with a halogen and a base to form a chiral halide of the formula (III) wherein X1, X2 and R are as defined above, and X3 is Cl, Br or I; and (b) treating the halide of formula (III) of Step (a) with an alkali metal triazole to form a chiral triazole compound of the formula (III), wherein X3 is triazolyl; removing the protecting group R from the triazole compound to form an alcohol of the formula (III), wherein X is triazolyl and R is H; and treating the alcohol with a compound of the formula E-X, wherein X is Cl or Br, and E is as defined above, to form the compound of formula (I); or (bi) removing the protecting group R from the halide of formula (III) of Step (a) to form an alcohol of the formula (III), wherein R is H;
treating the alcohol with an alkali metal triazole to form a chiral triazole compound of the formula (III), wherein X3 is triazolyl and R
is H; and treating the alcohol with a compound of the formula E-X, wherein X is Cl or Br, and E is as defined above, to form the compound of formula (I).
2. A process according to claim 1 wherein R is -C(O)R1, and the starting compound of formula (II) of Step (a) is prepared by selectively esterifying a prochiral diol of the formula (IV) by reacting the diol (IV) with an effective amount of a mild acylating agent in the presence of an enzyme to form the chiral hydroxy ester of formula (IIa) wherein X1 and X2 are as defined above, and R1 is C1-C6 alkyl.
3. A process according to claim 1 wherein R is -C(O)R1, and the chiral hydroxy ester of formula (II) of Step (a) is prepared by a process comprising the steps:
(i) esterifying the prochiral diol of formula (IV) with an amount of an acylating agent effective to form a diester of the formula (V) wherein X1, X2 and R1 are as defined above; and (ii) stereoselectively hydrolyzing the diester of formula (V) of Step (i) in the presence of an enzyme to form a chiral hydroxy ester of the formula (IIa) wherein X1, X2 and R1 are as defined above.
4. A process according to claim 2 wherein the prochiral diol of the formula (IV) is prepared via a process comprising the steps:
(A1) converting an allylic alcohol of the formula (VI) wherein X1 and X2 are as defined above, to a compound of the formula (VII) wherein X1 and X2 are as defined above and L1 is a leaving group selected from Br, -OSO2CH3 and -OSO2C6H4CH3;
(A2) reacting the product of Step (A1) with an amount of an alkali metal salt of the anion derived from a di(C1-C6 alkyl)malonate effective to form a diester of the formula (VIII) wherein X1 and X2 are as defined above, and R2 is C1-C6 alkyl;
(A3) treating the diester of the formula (VIII) of Step (A2) with an amount of a hydride reducing agent effective to form the prochiral diol of the formula (IV).
5. A process according to claim 3 wherein the prochiral diol of the formula (IV) is prepared via a process comprising the steps:
(A1) converting an allylic alcohol of the formula (VI) wherein X1 and X2 are as defined above, to a compound of the formula (VII) wherein X1 and X2 are as defined above and L1 is a leaving group selected from Br, -OSO2CH3 and -OSO2C6H4CH3;
(A2) reacting the product of Step (A1) with an amount of an alkali metal salt of the anion derived from a di(C1-C6 alkyl)malonate effective to form a diester of the formula (VIII) wherein X1 and X2 are as defined above, and R2 is C1-C6 alkyl;
(A3) treating the diester of the formula (VIII) of Step (A2) with an amount of a hydride reducing agent effective to form the prochiral diol of the formula (IV).
6. A process according to claim 1 wherein the chiral alcohol of formula (II) of Step (a), wherein R
is -CH2-C6H5, is prepared by a process comprising the steps :
(B1) reacting a compound of the formula (IX) wherein X1 and X2 are as defined above and Q* is a chiral auxiliary group, with a compound of the formula C6H5-CH2-O-CH2-L, wherein L is a leaving group selected from Cl, Br and I, in the presence of TiCl4 and a tertiary amine base, in amounts effective to form a chiral compound of the formula (X) wherein X, X2 and Q* are as defined above; and (B2) treating the product of formula (X) of Step (B1) with an amount of LiAlH4 effective to form a chiral compound of the formula (II) wherein R is -CH2C6H5.
7. A process according to claim 6 wherein the starting compound of the formula (IX) is prepared by a process comprising the steps:
(B3) heating an allylic alcohol of the formula (VI) wherein X1 and X2 are as defined above, with effective amounts of CH3C(OC2H5) 3 and C2H5CO2H, followed by treatment with an amount of a hydroxide base effective to form an acid of the formula (XI) wherein X1 and X2 are as defined above; and (B4) treating the acid of formula (XI) of Step (B3) with an effective amount of an activating agent, then with an alkali metal salt of the formula M+-Q*, wherein M+ is an alkali metal cation and -Q* is the anion derived from a compound of the formula HQ*, wherein Q* is as defined above, to form a compound of the formula (IX).
8. A process for preparing compounds of the formula (I) wherein: X1 and X2 are independently F or Cl: and E is -SO2 R2, wherein R2 is C1-C6 alkyl, -C6H4CH3 or -CF3:
comprising the steps:
(D1) esterifying a chiral alcohol of the formula (II) wherein X1 and X2 are as defined above, and R is -CH2-C6H5, by treating with an effective amount of an acylating agent to form a chiral compound of the formula (XIX) wherein X1, X2 and R are as defined above and R1 is C1-C6 alkyl;
(D2) cyclizing the chiral product of formula (XIX) of Step (D1) by treating with a halogen to form a chiral halide of the formula (III) wherein X1, X2 are as defined above, R is -C(O)R1, R1 is as defined above and X3 is Cl, Br or I; and (b) treating the halide of formula (III) of Step (D2) with an alkali metal triazole to form a chiral triazole compound of the formula (III), wherein X3 is triazolyl: removing the protecting group R from the triazole compound to form an alcohol of the formula (III), wherein X is triazolyl and R is H; and treating the alcohol with a compound of the formula E-X, wherein X is Cl or Br, and E is as defined above, to form the compound of formula (I); or (bi) removing the protecting group R from the halide of formula (III) of Step (a) to form an alcohol of the formula (III), wherein R is H;
treating the alcohol with an alkali metal triazole to form a chiral triazole compound of the formula (III), wherein X3 is triazolyl and R
is H; and treating the alcohol with a compound of the formula E-X, wherein X is Cl or Br, and E is as defined above, to form the compound of formula (I).
9. A process according to claim 1 wherein:
(a) in Step (a) : the halogen is Br2 or I2 ;
the base is pyridine or NaHCO3; and the cyclization is carried out in the presence of a solvent selected from CH3CN, tetrahydrofuran, ethyl acetate and CH2Cl2; and (b) in Step (b):
(1) the alkali metal triazole is sodium triazole, and the triazole treatment is carried out in the presence of DMPU and N,N-dimethylformamide at 70° to 100°C; and (2) the protecting group R is removed from the triazole compound by:
(i) where R is -C (O) R1, and R1 is C1-C6 alkyl, treating with a base selected from K2CO3, Na2CO3 and NH4OH, in the presence of methanol and water at 0° to 25°C; or (ii) where R is tetrahydropyran-2-yl, treating with HCl and water at 15° to 35°C;
or (iii) where R is -CH2C6H5, hydrogenating in the presence of a Pd on carbon catalyst, an acid, and ethanol; to form the alcohol wherein R is H and X3 is triazolyl; or (b1) in Step (b1):
(1) the protecting group R is removed by:
(i) where R is -C(O)R1, and R1 is C1-C6 alkyl, treating with a base selected from K2CO3, Na2CO3 and NH4OH, in the presence of methanol and water at 0° to 25°C; or (ii) where R is tetrahydropyran-2-yl, treating with HCl and water at 15° to 35°C;
or (iii) where R is -CH2C6H5, hydrogenating in the presence of a Pd on carbon catalyst, an acid, and ethanol; and (2) the alkali metal triazole is sodium triazole, and the triazole treatment is carried out in the presence of DMPU and N,N-dimethylformamide at 70° to 100°C; to form the alcohol wherein R is H and X3 is triazolyl; and (3) the treatment with E-X is carried out in the presence of pyridine, and X is C1.
10. A process according to claim 2 wherein: the mild acylating agent is selected from vinyl acetate, isopropenyl acetate, methyl acetate and ethyl acetate;
and the enzyme is selected from Amano CE (Humicloa lanugiosa), Amano AY-30, Biocatalysts H. lanugiosa, Biocatalysts M. meihei, Biocatalysts Ps. fluorescens, Meito MY, Meito PL, Novo Lipozyme IM-20, and Novo SP435 (Candida antartica).
11. A process according to claim 3 wherein: the acylating agent is selected from butyric anhydride, acetic anhydride or acetyl chloride; and the enzyme is selected from Amano CE (Humicloa lanugiosa), Amano AY-30, Biocatalysts H. lanugiosa, Biocatalysts M. meihei, Biocatalysts Ps. fluorescens, Meito MY, Meito PL, Novo Lipozyme IM-20, and Novo SP435 (Candida antartica).
12. A process according to claim 4 wherein :
in Step (A1), the converting is effected by treating with a brominating agent or a sulfonylating agent;
in Step (A2), the alkali metal salt is a sodium salt and the dialkylmalonate is diethylmalonate; and in Step (A3), the hydride reducing agent is LiAlH4 or LiBH4.
13. A process according to claim 5 wherein:
in Step (A1), the converting is effected by treating with a brominating agent or a sulfonylating agent;
in Step (A2), the alkali metal salt is a sodium salt and the dialkylmalonate is diethylmalonate; and in Step (A3), the hydride reducing agent is LiAlH4 or LiBH4.
14. A process according to claim 6 wherein in Step (B1), L is C1, the tertiary amine base is triethylamine, and the chiral auxiliary Q* is an oxazolidinone of the formula wherein R5 is isopropyl.
15. A process according to claim 7 wherein: in Step (B3), the hydroxide base is KOH or NaOH; and in Step (B4), the activating agent is oxalyl chloride or SOCl2, M+ is Li+, and -Q+ is wherein R5 is isopropyl.
16. A process according to claim 8 wherein: in Step (D1), the acetylating agent is acetic anhydride;
and in Step (D2), the halogen is I2.
CA002161662A 1993-04-30 1994-04-28 Process for preparing intermediates for the synthesis of antifungal agent Expired - Fee Related CA2161662C (en)

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US5703236A (en) * 1993-12-21 1997-12-30 Schering Corporation Tetrahydrofuran antifungals
US5486625A (en) * 1994-07-08 1996-01-23 Schering Corporation Process for the preparation of chiral intermediates useful for the synthesis of antifungal agents
ES2112151B1 (en) * 1995-03-17 1999-09-16 Menarini Lab NEW HOMOQUIRAL COMPOUNDS FOR THE PREPARATION OF KETOCONAZOLE, THERONAZOLE AND RELATED ANTIFUNGICS, PROCEDURE FOR THEIR MANUFACTURE AND USE OF THEM.
US5625064A (en) * 1995-04-19 1997-04-29 Schering Corporation Process for the preparation of triazolones
US5616777A (en) * 1995-04-19 1997-04-01 Schering Corporation Chiral hydrazine derivatives
US5756830A (en) * 1995-12-20 1998-05-26 Schering Corporation Process for preparing intermediates for the synthesis of antifungal agents
ES2187684T3 (en) * 1995-12-20 2003-06-16 Schering Corp PROCEDURE TO PREPARE INTERMEDIATE PRODUCTS FOR THE SYNTHESIS OF ANTIFUNGIC AGENTS.
KR100326276B1 (en) * 1999-12-14 2002-03-08 정명식 Tetrahydrofurane derivatives, producing method thereof and antifungals comprising the same
AU2011254658B2 (en) * 2010-05-19 2016-02-18 Sandoz Ag Purification of posaconazole and of posaconazole intermediates
WO2011144656A1 (en) 2010-05-19 2011-11-24 Sandoz Ag Preparation of posaconazole intermediates
CN102892750B (en) 2010-05-19 2016-03-02 桑多斯股份公司 Prepare the method for chirality hydrazides
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CA2838051C (en) 2011-06-16 2019-09-24 Sandoz Ag Process for the preparation of a chiral compound
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